Oxygen consumption is a fundamental component of metabolic networks, mitochondrial function, and global carbon cycling. To date there is no method available that allows for replicate measurements on attached and unatt...Oxygen consumption is a fundamental component of metabolic networks, mitochondrial function, and global carbon cycling. To date there is no method available that allows for replicate measurements on attached and unattached biological samples without compensation for extraneous oxygen leaking into the system. Here we present the Respiratory Detection System, which is compatible with virtually any biological sample. The RDS can be used to measure oxygen uptake in microliter-scale volumes with a reversibly sealed sample chamber, which contains a porphyrin-based oxygen sensor. With the RDS, one can maintain a diffusional seal for up to three hours, allowing for the direct measurement of respiratory function of samples with fast or slow metabolic rates. The ability to easily measure oxygen uptake in small volumes with small populations or dilute samples has implications in cell biology, environmental biology, and clinical diagnostics.展开更多
Marine heatwaves(MHWs)caused by anthropogenic climate change are becoming a key driver of change at the ecosystem level.Thermal conditions experienced by marine organisms across their distribution,particularly towards...Marine heatwaves(MHWs)caused by anthropogenic climate change are becoming a key driver of change at the ecosystem level.Thermal conditions experienced by marine organisms across their distribution,particularly towards the equator,are likely to approach their physiological limits,resulting in extensive mortality and subsequent changes at the population level.Populations at the margins of their species’distribution are thought to be more sensitive to climate-induced environmental pressures than central populations,but our understanding of variability in fitness-related physiological traits in trailing versus leading-edge populations is limited.In a laboratory simulation study,we tested whether two leading(Iceland)and two trailing(Spain)peripheral populations of the intertidal macroalga Corallina officinalis display different levels of maximum potential quantum efficiency(Fv/Fm)resilience to current and future winter MHWs scenarios.Our study revealed that ongoing and future local winter MHWs will not negatively affect leading-edge populations of C.officinalis,which exhibited stable photosynthetic efficiency throughout the study.Trailing edge populations showed a positive though non-significant trend in photosynthetic efficiency throughout winter MHWs exposure.Poleward and equatorward populations did not produce significantly different results,with winter MHWs having no negative affect on Fv/Fm of either population.Additionally,we found no long-term regional or population-level influence of a winter MHWs on this species’photosynthetic efficiency.Thus,we found no statistically significant difference in thermal stress responses between leading and trailing populations.Nonetheless,C.officinalis showed a trend towards higher stress responses in southern than northern populations.Because responses rest on a variety of local population traits,they are difficult to predict based solely on thermal pressures.展开更多
Nucleotide compounds like sofosbuvir,acyclovir,and tenofovir have proven to be amongst the most potent orally available antiviral treatments.These drugs exhibit high efficacy and a wide therapeutic index,with demonstr...Nucleotide compounds like sofosbuvir,acyclovir,and tenofovir have proven to be amongst the most potent orally available antiviral treatments.These drugs exhibit high efficacy and a wide therapeutic index,with demonstrated utility in a number of chronic viral infections.The approval of SovaldiTM,brand name for sofosbuvir,by the U.S.Food and Drug Administration heralded improvements in chronic hepatitis C virus (HCV) treatment.Sofosbuvir was originally discovered by Pharmasset Corporation and named PSI-7977.It was subsequently acquired and advanced through phase 3 development by Gilead Sciences,Inc.In Sofosbuvir both a unique pharmacology and a high specificity for the HCV ribonucleic acid polymerase are present in a molecule that is well tolerated and highly efficacious.Phase 2 and 3 clinical trials have consistently demonstrated durable and high rates of sustained virologic response (SVR),curing patients in excess of 80% in all genotypes and >90% in treatment-na(i)ve subjects being administered combination therapy with other agents.Harvoni~ is the combination of sofosbuvir and the NS5A inhibitor ledipasvir in a fixed-dose oral tablet,and it has demonstrated high SVR rates in patients infected with HCV genotype 1,without the need for exogenous interferon and/or ribavirin.Here,we discuss the discovery,development,pharmacologic characterization,and results from the phase 3 trials of sofosbuvir.Hepatitis C is a chronic disease,for which most patients have been undiagnosed,are unwilling to start treatment,or are ineligible for treatment because of the high toxicity and low efficacy of interferon and ribavirin-based therapy.Clinical studies with sofosbuvir have demonstrated significant improvement over the prior standard of care,thus ushering in a new paradigm of HCV treatment and an update of treatment guidelines.展开更多
The realization of a mixed-phase microstructure in strained BiFeO_(3)(BFO)thin films has led to numerous novel effects derived from the coexistence of the tetragonal-like monoclinic phase(T phase)and rhombohedral-like...The realization of a mixed-phase microstructure in strained BiFeO_(3)(BFO)thin films has led to numerous novel effects derived from the coexistence of the tetragonal-like monoclinic phase(T phase)and rhombohedral-like monoclinic phase(R phase).Strong strain and polarization diiferences between the phases should result in a high level of transformation plasticity,which enables the continuous alteration of the relative proportion of R and T states in response to external forces.Although the potential for utilizing such plasticity to control mixed-phase populations under external stimuli is evident,direct experi・mental evidence backed by equilibrium predictions has not yet been fully demonstrated.Here we demonstrate deterministic control of mixed-phase populations in an epitaxially strained BFO thin film through the application of localized stresses and electric fields in a reversible manne匚The results illustrate and rationalize deterministic control of mixed phases in strained BFO films,which could be crucial in tuning their functional properties.The findings also highlight a new multiparametric technique in the scanning probe lithography toolbox based on tip-assisted electric and strain field manipulation of functional properties that might find application beyond the ferroelectric domain and structural phase lithography.展开更多
Objectives: To simultaneously examine adherence to long-term controller and quick-relief medications and to contrast patterns of medication use in children with asthma.Study design: Cross-sectional, 1-month follow-up ...Objectives: To simultaneously examine adherence to long-term controller and quick-relief medications and to contrast patterns of medication use in children with asthma.Study design: Cross-sectional, 1-month follow-up study conducted with 75 children ages 8 to 16 years diagnosedwith persistent asthma and prescribed quick-relief and long-term controller medications by metered dose inhaler.Participants were a subsample of a larger adherence study.The primary outcome measure was adherence to both medications as measured by electronic monitoring devices.A classification framework for contrasting adherence patterns between medication classes was developed to identify cases for individual analysis.Results: High levels of nonadherence to long-term controller medications (median = 46%of prescribed doses taken) and variable patterns of quick-relief medication use (range = 0 to 251 doses over the month) were documented,whereas consistent relationships between patterns of medication use across both classes were not found.Individual cases identified by the classification scheme illustrated the complexity and clinical utility of contrasting adherence patterns.Conclusions: Monitoring long-term controller medication adherence may be more predictive of morbidity than quick-relief medication use, except in outlier cases in which monitoring both medication types may be valuable for clinical and empirical purposes.展开更多
文摘Oxygen consumption is a fundamental component of metabolic networks, mitochondrial function, and global carbon cycling. To date there is no method available that allows for replicate measurements on attached and unattached biological samples without compensation for extraneous oxygen leaking into the system. Here we present the Respiratory Detection System, which is compatible with virtually any biological sample. The RDS can be used to measure oxygen uptake in microliter-scale volumes with a reversibly sealed sample chamber, which contains a porphyrin-based oxygen sensor. With the RDS, one can maintain a diffusional seal for up to three hours, allowing for the direct measurement of respiratory function of samples with fast or slow metabolic rates. The ability to easily measure oxygen uptake in small volumes with small populations or dilute samples has implications in cell biology, environmental biology, and clinical diagnostics.
基金The Fundação para a Ciência e Tecnologia(FCT-MEC,Portugal)under contract No.UIDB/04326/2020 awarded to Gerardo Zardithe South African Research Chairs Initiative(SARChI)of the Department of Science and Technology and the National Research Foundation of South Africa under contract No.64801 awarded to Christopher McQuaid+1 种基金the Fund of European Union’s Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie contract No.101034329the WINNINGNormandy Program supported by the Normandy Region for Gerardo Zardi.
文摘Marine heatwaves(MHWs)caused by anthropogenic climate change are becoming a key driver of change at the ecosystem level.Thermal conditions experienced by marine organisms across their distribution,particularly towards the equator,are likely to approach their physiological limits,resulting in extensive mortality and subsequent changes at the population level.Populations at the margins of their species’distribution are thought to be more sensitive to climate-induced environmental pressures than central populations,but our understanding of variability in fitness-related physiological traits in trailing versus leading-edge populations is limited.In a laboratory simulation study,we tested whether two leading(Iceland)and two trailing(Spain)peripheral populations of the intertidal macroalga Corallina officinalis display different levels of maximum potential quantum efficiency(Fv/Fm)resilience to current and future winter MHWs scenarios.Our study revealed that ongoing and future local winter MHWs will not negatively affect leading-edge populations of C.officinalis,which exhibited stable photosynthetic efficiency throughout the study.Trailing edge populations showed a positive though non-significant trend in photosynthetic efficiency throughout winter MHWs exposure.Poleward and equatorward populations did not produce significantly different results,with winter MHWs having no negative affect on Fv/Fm of either population.Additionally,we found no long-term regional or population-level influence of a winter MHWs on this species’photosynthetic efficiency.Thus,we found no statistically significant difference in thermal stress responses between leading and trailing populations.Nonetheless,C.officinalis showed a trend towards higher stress responses in southern than northern populations.Because responses rest on a variety of local population traits,they are difficult to predict based solely on thermal pressures.
文摘Nucleotide compounds like sofosbuvir,acyclovir,and tenofovir have proven to be amongst the most potent orally available antiviral treatments.These drugs exhibit high efficacy and a wide therapeutic index,with demonstrated utility in a number of chronic viral infections.The approval of SovaldiTM,brand name for sofosbuvir,by the U.S.Food and Drug Administration heralded improvements in chronic hepatitis C virus (HCV) treatment.Sofosbuvir was originally discovered by Pharmasset Corporation and named PSI-7977.It was subsequently acquired and advanced through phase 3 development by Gilead Sciences,Inc.In Sofosbuvir both a unique pharmacology and a high specificity for the HCV ribonucleic acid polymerase are present in a molecule that is well tolerated and highly efficacious.Phase 2 and 3 clinical trials have consistently demonstrated durable and high rates of sustained virologic response (SVR),curing patients in excess of 80% in all genotypes and >90% in treatment-na(i)ve subjects being administered combination therapy with other agents.Harvoni~ is the combination of sofosbuvir and the NS5A inhibitor ledipasvir in a fixed-dose oral tablet,and it has demonstrated high SVR rates in patients infected with HCV genotype 1,without the need for exogenous interferon and/or ribavirin.Here,we discuss the discovery,development,pharmacologic characterization,and results from the phase 3 trials of sofosbuvir.Hepatitis C is a chronic disease,for which most patients have been undiagnosed,are unwilling to start treatment,or are ineligible for treatment because of the high toxicity and low efficacy of interferon and ribavirin-based therapy.Clinical studies with sofosbuvir have demonstrated significant improvement over the prior standard of care,thus ushering in a new paradigm of HCV treatment and an update of treatment guidelines.
基金UK Research and Innovation,MR/T043172/1Raymond G.P.McQuaid+4 种基金Department for Employment and Learning,Northern Ireland,USI-082Amit KumarEngineering and Physical Sciences Research Council,EP/S037179/1Amit KumarEP/LO15323/01,Nathan Black.
文摘The realization of a mixed-phase microstructure in strained BiFeO_(3)(BFO)thin films has led to numerous novel effects derived from the coexistence of the tetragonal-like monoclinic phase(T phase)and rhombohedral-like monoclinic phase(R phase).Strong strain and polarization diiferences between the phases should result in a high level of transformation plasticity,which enables the continuous alteration of the relative proportion of R and T states in response to external forces.Although the potential for utilizing such plasticity to control mixed-phase populations under external stimuli is evident,direct experi・mental evidence backed by equilibrium predictions has not yet been fully demonstrated.Here we demonstrate deterministic control of mixed-phase populations in an epitaxially strained BFO thin film through the application of localized stresses and electric fields in a reversible manne匚The results illustrate and rationalize deterministic control of mixed phases in strained BFO films,which could be crucial in tuning their functional properties.The findings also highlight a new multiparametric technique in the scanning probe lithography toolbox based on tip-assisted electric and strain field manipulation of functional properties that might find application beyond the ferroelectric domain and structural phase lithography.
文摘Objectives: To simultaneously examine adherence to long-term controller and quick-relief medications and to contrast patterns of medication use in children with asthma.Study design: Cross-sectional, 1-month follow-up study conducted with 75 children ages 8 to 16 years diagnosedwith persistent asthma and prescribed quick-relief and long-term controller medications by metered dose inhaler.Participants were a subsample of a larger adherence study.The primary outcome measure was adherence to both medications as measured by electronic monitoring devices.A classification framework for contrasting adherence patterns between medication classes was developed to identify cases for individual analysis.Results: High levels of nonadherence to long-term controller medications (median = 46%of prescribed doses taken) and variable patterns of quick-relief medication use (range = 0 to 251 doses over the month) were documented,whereas consistent relationships between patterns of medication use across both classes were not found.Individual cases identified by the classification scheme illustrated the complexity and clinical utility of contrasting adherence patterns.Conclusions: Monitoring long-term controller medication adherence may be more predictive of morbidity than quick-relief medication use, except in outlier cases in which monitoring both medication types may be valuable for clinical and empirical purposes.
